Award details

A Sexually-dimorphic Brain Module for Sensory Integration

Reference	BB/T001348/1
Principal Investigator / Supervisor	Professor Stephen Goodwin
Co-Investigators / Co-Supervisors	Dr Tetsuya Nojima
Institution	University of Oxford
Department	Physiology Anatomy and Genetics
Funding type	Research
Value (£)	375,778
Status	Current
Type	Research Grant
Start date	01/11/2019
End date	31/10/2023
Duration	48 months

Abstract

Our dsx map enabled us to predict potential entry points for dimorphisms in sensory processing between the sexes. A glutamatergic cluster called aDN is particularly interesting due to its apparent sex-specific connectivity. Investigating its input sites, we found that in males these neurons extend their input sites to a region called the anterior optic tubercle (AOTu), while in females input sites are associated with the superior lateral protocerebrum (pSLP). The AOTu is one of the optic glomeruli, in which visual projection neurons (VPNs) in the optic lobe send visual information to the central brain, and is known to mediate visual processing in other insects, while the pSLP is unrelated to any known optic glomeruli, suggesting a connectivity difference in the central processing of information between the sexes. We will test the role of neural activity in aDN neurons in males and females; using optogenetic stimulation and GCaMP imaging to establish functional connectivity and understand its physiological relevance. These experiments will establish whether network architecture and/or calcium dynamics across the network display sexual dimorphism. We will test the behavioural relevance of these neurons, and how these circuit differences relate to sex-specific behavioural displays. The specific aims of the proposal are: 1) Functionally establish sex-specific aDN sensory inputs 2) Examine the behavioural functions of aDN circuit elements 3) Identify and functionally connect aDN neurons to downstream circuit elements

Summary

The complex interplay between a male and female of a species during courtship is one of the most remarkable examples of sexually dimorphic behaviour in the animal kingdom. Upon identifying a suitable partner, Drosophila melanogaster males initiate an elaborate courtship ritual that culminates with copulation. Drosophila females do not actively court males, yet it is her response to the male's advances that determines whether mating will actually occur. These are complex decisions and behaviours controlled by the brain, but working with flies has the advantage of using a vast array of genetic tools that allows us to identify and manipulate relevant neurons in the brain. With these tools we can ask how does the brain differ between the sexes, and how might these differences explain the distinct behaviours of males and females that are critical for reproductive success? Sexually reproducing species exhibit sex differences in social interactions, ostensibly to boost reproductive success and survival of progeny. A core set of sex-typical behavioural displays such as mating, and aggression, although modifiable by experience, are innate in the sense that they can be displayed without prior training. How does an animal's biological sex instruct the behavioural response? Males and females transform sensory input into sexually dimorphic behaviours, suggesting that such behaviours are generated by neural circuits that differ between the sexes These sexual dimorphisms in innate behaviour reflect the action of a sexually differentiated nervous system. Animals determine sex early in their development, and sex determination initiates many irreversible sexual differentiation events that influence how the genome and the environment interact to give rise to sex-specific behaviours. Across taxa, such mechanisms converge to regulate sexually dimorphic gene expression that in turn specifies sex-typical development and neural circuit function. In the fly, sex-specific behaviours are hardwired into the nervous system via the actions of two sex determination transcription factors (TFs), Doublesex (Dsx) and Fruitless (Fru). We have focused our attention on neurons that express these TFs to find anatomical or molecular sex differences in neuronal populations in order to gain an entry point into the neural circuits underlying gender-typical behaviours and identify the neuronal nodes that control component behaviours and behavioural sequencing. Alternative neural circuit wiring configurations have been proposed to generate sexually dimorphic behaviours. Neurons present only in one sex (qualitative sex difference) may either activate or inhibit a sexually dimorphic behaviour in that sex. More commonly in invertebrates and vertebrates, a neuronal population is present in both sexes but presents sex differences (quantitative sex difference) in physiology, neuron number, or connectivity. In such cases, the neurons may regulate the probability of displaying a sexually dimorphic behaviour, or control the display of different sexually dimorphic behaviours in the two sexes (functionally bivalent). We have focused on the role of neurons that express dsx. These dsx+ neurons control male courtship behaviour and aspects of female receptivity. Yet little is known about the specific role of dsx+ neurons in the brain, which are believed to control mating decisions. We identified a group of sexually-dimorphic dsx neurons that are critical to sensory integration in males and females. Importantly, the dimorphism we uncovered can alter connectivity and information flow between males and females, where a dedicated visual pathway processing sex-specific visual cues has evolved in males, but not females. Our goal is to understand how neural circuits in general, and sexually dimorphic neurons in particular, can generate sexually dimorphic behaviours, and how molecular mechanisms and evolutionary constraints shape these behaviours.

Impact Summary

Who will benefit from this research proposal? Discoveries in Drosophila have greatly contributed to our understanding of neuroscience. An unequalled wealth of genetic techniques and strategies has permitted landmark discoveries in nervous system development and function. Such findings have generated and directed many research efforts in vertebrate neuroscience. After 100 years, Drosophila continues to be the choice model system for many neuroscientists. The combinational use of powerful research tools will ensure that this model organism will continue to lead to key discoveries that will impact vertebrate neuroscience. Moreover, working with Drosophila means less use of vertebrate models, saving on housing and husbandry costs as well as ethical considerations. This has long been a goal of the UK Research Councils and of society at large and falls under the aims of the 3Rs programme: replacement, reduction and refinement. We are using the Drosophila nervous system to study behavioural choices during courtship. Because the Drosophila nervous system is more accessible experimentally, and has fewer neurons than vertebrate brains, we believe it will yield insights into the mechanisms of behavioural choice that are much harder to study in higher vertebrates. Moreover, discoveries that contribute to our understanding of reproductive behaviours in Drosophila are particularly important to other dipteran insects of medical importance. For example, mosquitoes and mosquito-borne diseases continue to plague mankind throughout the world. Of the critical behaviours that characterise the mosquito life strategy, mating is probably the least understood and most understudied. As mosquitoes depend on sexual reproduction for species maintenance, this aspect of mosquito biology is receiving much attention for mosquito control and interventions for mosquito-borne disease. For example, and with direct relevance to this grant, a CRISPR-Cas9 gene drive targeting the doublesex gene caused complete population suppression in caged Anopheles gambiae mosquitoes (Nature Biotechnology, 36,1062-1066: 2018). How might individuals, organisations or society benefit from this research? Sexually reproducing species often exhibit gender dimorphisms in behaviours such as courtship, aggression, and parental care. Defining the mechanisms underlying sexual differentiation of the brain and behaviour is one of biology's greatest challenges. Communicating how and why we use model organisms to study these basic mechanisms common to many forms of life is extremely important. S.F.G. has undertaken outreach activities with local schools, particularly during Science Week; presented his lab's work through Café Scientifique (http://www.cafescientifique.org) a forum for debating science issues, which is committed to promoting public engagement with science and to making science accountable; participated in the Channel4 BRITDOC-Festival, which brings together researchers, with some of the UK's foremost documentary filmmakers to exchange ideas and explore the potential for collaborations; and participated in Perspectives in Biology at Wake Forest University in 2018 (http://college.wfu.edu/biology/news-and-events/perspectives-in-biology/), a symposium that has been running for 34 years in the US, for professors from community colleges and technical schools to get subject specific professional training in contemporary biology. This proposal has not only the potential for medically relevant discoveries but will also produce simple, yet provocative experimental paradigms, and discussion groups for teaching school children, undergraduates, postgraduates and faculty alike.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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